The present invention relates to a process for preparation of N-substituted heterocyclic derivative,2-n-Butyl-4-chloro-l-{ [2'-(2-triphenylmethyl-2H-tetrazole-5-yl)-1, 1 '-biphenyl -4-yl] methyl} -lH-imidazole-5-methanol, an important intermediate in the synthesis of Losartan and its pharmaceutically acceptable salts using phase transfer catalyst and minimal number of solvents with improved yield.

Full Text

Field of the Invention:
The present invention relates to a process for preparation of N-substituted heterocyclic derivative,2-n-Butyl-4-chloro-1 - {[2' -(2-triphenylmethyl-2H-tetrazole-5-yl)-1, T -biphenyl -4-yl] methyl} -1 H-imidazole-5-methanol (an intermediate of Losartan and its pharmaceutically acceptable salts).
Background of the Invention:
2-n-butyl-4-chlorol-{[2^-(2-methyl-2H4etrazole-5-yl)-l,r-biphenyl"4-yl]methyl}-lH^ imidazole-5-methanol (Losartan) has the structure as given below

Losartan
Losartan and its pharmaceutically acceptable sahs are useful as antagonists of the peptide hormone angiotensin IL Angiotensin II is a potent vasopressor and the biologically active product of the rermin-angiotensin system. Thus Losartan is useful in the treatment of hypertension and congestive heart failure.
European Patent No. EP 253,310 discloses a synthetic route for the preparation of 2-n-Butyl-4-chloro-1 - {[2^ -(2-triphenylmethyl"2H-tetrazole-5-yl)-1, r -biphenyl-4-yl]methyl} -lH-imidazole-5-methanol, which involves the condensation of 2-n-Butyl-4-chloroimidazole-5 -carboxaldehyde with 5 -(4' -Bromomethyl-1, T -biphenyl-2-yl)-1 -(triphenylmethyl)-lH-tetrazole in a solvent such as alcohol, DMF or DMSO, in a basic medium, for example in the presence of sodium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine, or a metal alcoholate such as sodium methoxide, sodium ethoxide. The EP 253,310 further discloses the usage of phase transfer conditions in the condensation reaction.

U.S. Patent No. 5,310,928 discloses a process for preparation of 2-n-Butyl-4-chloro-l-{[2'-(2-triphenylmethyl-2H-tetrazole-5-yl)-1, T-biphenyl-4-yl] methyl}-1 H-imidazole-5-methanol by the condensation of 2-n-Butyl-4-chloroimidazole"5-carboxaldehyde with 5-(4'-Bromomethyl-1,T-biphenyl-2-yl)-1 -(triphenylmethyl)-1 H-tetrazole in presence of potassium carbonate in N,N-Dimethyl acetamide as solvent followed by reduction with sodium borohydride, with or without isolation of the intermediate 2-n-Butyl-4-chloro-l-{[2' -(2-triphenylmethyl-2H-tetrazole-5-yl)-1, T -biphenyl-4-yl] methyl} -1 H-imidazole-5-carboxaldehyde and crystall- ization from butyl chloride followed by recrystallization with ethyl acetate in a overall yield of 72%.
European Patent No. EP 324,377 discloses a process for the preparation of 2-n-Butyl-4-chloro-1 - {[2' -(2-tripheny lmethyl-2H-tetrazole-5 -yl)-1, T -biphenyl-4-yl] methyl} -1H-imidazole-5-methanol by condensation of 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde with 5-(4' "Bromomethyl-1, T -biphenyl-2-yl)-1 -(tri phenylmethyl)-1 H-tetrazole in presence of sodium hydroxide, water, methylene dichloride, carbon tetra chloride followed by reduction with sodium borohydride, isolation by distillation of solvents, addition of toluene and dilution with ethyl acetate, n-heptane in a overall yield of 51.7%.
J.Med.Chem. 34 (1991) 2538 discloses a process for preparation of 2-n-Butyl-4-chloro-l-{[2'-(2"triphenylmethyl-2H-tetrazole-5-yl)-1, T-biphenyl-4-yl] methyl} -1 H-imidazole-5-carboxaldehyde by condensation of 2-n"Butyl-4-chloroimidazole-5-carboxaldehyde with 5"(4'-Bromomethyl-1, T -biphenyl-2-yl)-1 -(triphenylmethyl)-1 H-tetrazole in presence of a base, tetrabutyl phosphonium bromide as a phase transfer catalyst in methylene chloride and water followed by concentration and crystallization with nitromethane in a overall yield of 59.3%.
All the above prior art processes describes the processes which involves the use of multiple solvents for the preparation, isolation and recrystallization of 2-n-Butyl-4-chloro-1- {[2^-(2-triphenyl methyl-2H-tetrazole-5-yl)-l,r-biphenyl-4-yl]methyl}-lH-imidazole-5-methanol from 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde,5-(4'-Bromo

methyl-l,r-biphenyl-2"yl)-l"(triphenylniethyl -IH-tetrazole or with low yields thereby increasing the operational cost of the product.
There is a long felt need of the industry to provide a process for the preparation of 2-n-Butyl-4-chloro-1 - {[2^ -(2-triphenylmethy l-2H-tetrazole-5 -yl)-1, r -biphenyl"4-yl]methyl} -IH-imidazole -5-methanol,important intermediate in the synthesis of Losartan v^thout involving the usage of multiple solvents and with improved yield.
Summary of the Invention:
The main object of the present invention is to provide a process for the preparation of N-substituted heterocyclic derivatives
Another object of the present invention is to provide a process for the preparation of 2-n" Butyl"4-chloro-l-{[2^-(2-triphenylmethyl-2H-tetrazole-5-yl)"l,r-biphenyl-4-yl]methyl}-IH-imidazole -5-methanol for its use in preparation of Losartan.
Another object of the present invention is to provide a process for preparation of 2-n-Butyl-4-chIoro-1 - {[2 ^ -(2-triphenylmethyl-2H-tetrazole-5-yI)-1, T -biphenyl-4-yl]methyl} -lH-imidazole-5-methanol without using multiple solvents.
Another object of the present invention is to provide a process for the preparation of 2-n" Butyl-4-chloro-l-{[2^-(2-triphenylmethyl-2H-tetrazole-5-yl)-l,r-biphenyl-4-yl]methyl}" IH-imidazole -5-methanoI using phase transfer catalyst.
Yet another object of the present invention is to provide a process for the preparation of 2-n-Butyl-4-chloro-1 - {[2^ -(2-triphenylmethyl"2H-tetrazole-5-yl)-1, T -biphenyl-4-yl]methyI}-lH-imidazole-5-methanol with improved yield.
Accordingly in the present invention (Scheme-I) 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde is condensed with 5-(4' -Bromo methyl-1, T -biphenyl-2-yl)-1 -(triphenylmethyl)-lH-tetrazole in water, halohydrocarbon in presence of base, phase transfer catalyst, followed by separation of organic layer, reduction with sodium borohydride and lower alcohol, isolation of the product by addition of water, separation

and concentration of the organic layer. The product can be recrystallized with ethyl acetate if necessary with an overall yield of about 80%.
Scheme-l

The prepared N-substituted heterocyclic derivatives 2-n-Butyl-4-chloro-1 - {[2' -(2-triphenylmethyl-2H-tetrazoIe-5-yl)-1, r-biphenyl-4-yl]methyl}-1 H-imidazole-5-methanol can be converted to losartan and its pharmaceutically acceptable salts by the prior art methods.
Detailed description of the Invention:
Thus in accordance with the present invention preparation of N-substituted heterocyclic derivative 2-n-Butyl-4-chloro-1 - {[2' -(2-tripheny Imethyl -2H-tetrazole-5-yl)-1,1'-biphenyl-4-yl]methyl}-lH-imidazole-5-methanol essentially comprises of the following steps.
- Reacting 2-n-Butyl-4-chloroimidazole-5-carboxaldehyde with 5-(4'-Bromomethyl-l,r-biphenyl-2-yl)-l-(triphenylmethyl)-lH-tetrazole in a mixture of water and halohydrocarbon in presence of base and phase transfer catalyst.
- Maintaining the reaction mass to completion

- Separating the aqueous layer
- Reacting the organic layer with sodium borohydride and lower alcohol
- Adding water to the reaction mass and separating the layers

5-(4'-Bromomethyl-l,r-biphenyl-2-yl)-l-(triphenylmethyl)-lH-tetrazole is suspended in
a mixture of aqueous solution of inorganic base such as sodium hydroxide, potassium
hydroxide, sodium carbonate or potassium carbonate preferably sodium hydroxide,
halohydrocarbon such as methylene chloride, ethylene dichloride, propylchloride, 1-
chlorobutane (n-Butylchloride) preferably 1-chlorobutane, phase transfer catalyst
selectively quaternary ammonium salts such as tetrabutylammonium bromide,
tetrabutylammonium chloride, triethylbenzylammonium bromide,
triethylbenzylammonium chloride, preferably tetrabutylammonium bromide is added to the reaction mass. 2-n-Butyl-4-chloro imidazole-5-carboxaldehyde is added in single lot or in small portions to the reaction mass and mixed for about 18 hrs to 48 hrs preferably for about 24 hrs to 36 hrs at temperature of about lO^C to about 65^C preferably at about 25°C to 35^C. Reaction mass is allowed to settle the layers, separated the organic layer at temperature of 35*^C to about 60^C, preferably at about 45°C to about 55*^0, extracted the aqueous layer with halo hydrocarbon, washed the combined organic layer with water.
Sodium borohydride is added to the organic layer at temperature of about lO^C to about 45^C, preferably at about 20°C to about 35^C under nitrogen atmosphere. Temperature of the reaction mass is raised to about 35°C to about 55^*0, selectively to about 40*^C to about 50°C, lower alcohol such as methanol, ethanol, isopropanol, propanol, preferably methanol, ethanol is added slowly over 15 min to about 120 min and maintained the reaction mass for about 2 hrs to 8 hrs at temperature of 35°C to about 55*^C, preferably at about 40*^0 to 50*^C. Water is added to the reaction mass, allowed to settle and separated the layers at temperature of 35°C to about 55°C, added additional quantity of halo hydrocarbon if required to the organic layer. Organic layer is washed with water at temperature of about 35'C to about 75*'C, preferably at about 50°C to about 65°C, and concentrated the organic layer to about 70% to about 40% of the original volume by distillation of solvent. Reaction mass is cooled to about 30°C to 50^C further cooled to about 20°C to about 35°C and water is slowly added. Reaction mass is cooled to about O^'C to about 20'C, preferably to 5*^0 to 15'C over 1 hr to 4 hrs and maintained for about 2 hrs to 8 hrs at temperature of O^'C to about 20^C, preferably at about 5*^C to about 15^C. Product is isolated by filtration, washed with chilled halohydrocarbon and dried at

about 45'*C to about 75*^0 afforded the 2-n-Butyl-4-chloro-l-{[2^-(2-triphenyimethyl-2H-tetrazole-5-yl)-l,r-biphenyl-4-yl]methyl}-lH-imidazole-5-methanoL
Optionally the wet cake of above 2-n-Butyl-4-chloro-l-{[2'-(2-triphenylmethyl-2H-
tetrazole-5-yl)-1, T -biphenyl-4-yl]methyl} -1 H-imidazole-5-methanol can be
recrystallized in ethyl acetate by dissolution at reflux temperature followed by cooling to about 10°C to about 15°C affords the pure compound with a overall yield of about 70% to 80%.
The required 2-n-Butyl-4-chioroimidazoie-5-carboxaldehyde and 5-(4'-Bromomethyl-1, r -biphenyl-2-yl)-1 -(triphenylmethyl)-1 H-tetrazole are prepared by the prior art methods.
The invention is further illustrated with the following example
Example-1: Preparation of 2-n-Butyl-4-chloro-l-{[2'-(2-triphenyl methyl-2H-tetrazole-5-yl)-1,r-biphenyl-4-yl]methyl}-1 H-imidazole -5-methanol.
5-(4' -Bromomethyl-1, T -biphenyl-2-yl)-1 -(triphenylmethyl)-1 H-tetrazole (100 g) is suspended in a mixture of 1-chlorobutane (600 ml)and IN sodium hydroxide (400 ml) at temperature of 25*^0 and tetra butyl ammonium bromide (lOg) is added. 2-n-Butyl-4-chloroimidazoie-5-carboxaldehyde (35g) is added in small portions to the reaction mass at temperature of 25*^0 to 30*^C and maintained the reaction mass for about 32 hrs at temperature of 25^C to 30°C. Temperature of the reaction mass is raised to 45°C to 50°C and allowed to settle the layers. Organic layer is separated, extracted the aqueous layer with 1-chloro butane (200 ml) and the combined organic layer is washed with water (200ml) at 45°C to SO^'C.The organic layer is cooled and sodium borohydride (7.4 g) is added at 25^C to 30*^C under nitrogen atmosphere. Reaction mass temperature is raised to 40^C to 45^C, methanol (50 ml) is added over 45 min and maintained the reaction mass at 40^C to 45*^C for 5hrs. Water (100 ml) is added to the reaction mass, allowed to settle and separated the layers at 40*^C to 45°C. 1-Chlorobutane (100 ml) is added to the organic layer, raised the temperature to 60*^0 to 65°C and washed with water (100 ml). Distilled off the solvent till reaction mass volume becomes around 600 ml. Cooled the reaction

mass to 28*^C. Water (100 ml) is added, cooled the reaction mass to lO^^C over 2 hrs and maintained at 10°C to 15*^C for 4 hrs. Filtered the product and washed with chilled 1-chloro butane (50 ml).
The wet cake (130g) is suspended in ethyl acetate (300 ml), raised the temperature to reflux, maintained for 30 min at reflux temperature. Slowly cooled the reaction mass to IS'^C and maintained at 14°C to \6^C for 3 hrs. Filtered the product, washed with ethyl acetate (100 ml) and dried at GO^'C - eS^'C till constant weight.
The dry weight of 2-n-Butyl-4-chIoro-l-{[2^-(2-triphenylmethyl-2H-tetrazole-5-yl)-l,r-biphenyl-4-yl]methyl}-lH-imidazole-5-methanol is 93.0 g (Yield: 78%)

7. The process as claimed in claim 1, wherein the separation of layers is carried out at
temperature of 35°C to 60'C.
8. The process as claimed in claim 1, wherein the reaction of organic layer with sodium
borohydride and lower alcohol is at temperature of 35^C to 55°C for 2 hrs to 8 hrs.
9. The process as claimed in claim 1 & 8 wherein the lower alcohol is methanol, ethanol,
propanol and isopropanol.
10. The process as claimed in claim 1, wherein the washing of organic layer with water is
carried out at 35*^0 to 75^C.
11. The process as claimed in claim 1, wherein the organic layer is concentrated to a
volume of 40% to 70% of its original volume.
12. The process as claimed in claim 1, wherein the product is isolated at 0*^C to 20^C
13. The process as claimed in claim 1, wherein recrystallization is carried out in ethyl acetate.
Dated: 05,10.2004 Hyderabad